The purpose of this study is to examine the long-term therapeutic role of glycogen synthase kinase-3 (GSK-3) inhibition in sustained traumatic brain injury (TBI) triggered by repetitive mild traumatic brain injury (rmTBI). Mild TBI (mTBI) comprises more than 75 % of all TBI. Among individuals with mTBI, a significant portion of them develop sustained TBI as the acute neuropathology of mTBI develops into chronic neurodegeneration. The acute neuropathology of mTBI initiates long apoptotic cascades leading to chronic neurodegenerative disorders with cognitive deficits such as chronic traumatic encephalopathy (CTE) and Alzheimer?s disease (AD). The major neuropathology of the neurodegenerative disorders includes neuronal death, gliosis and aggregation of phosphorylated tau protein (tauopathy) and ? amyloid (A?), which are considered to be the neuropathological landmarks of TBI. Among individuals with mTBI, those with repetitive concussions (rmTBI) are particularly susceptible to the risk of the chronic neurodenegerative disorders. GSK-3 constitutively inhibits neuroprotection and promotes apoptosis. AD research indicates that excessive GSK-3 activity accelerates tauopathy and A? deposit, impairment in hippocampal synaptic plasticity, the essential neurobiological basis of cognitive function, and cognitive deficits. GSK-3 inhibition attenuates tauopathy and A? formation, and improves hippocampal synaptic plasticity and cognitive deficits. Studies using rodent TBI models indicate that GSK-3 inhibition reverses the neurodegenerative processes of TBI, reduces tauopathy and A? deposit and improves cognitive deficits. Although these studies suggest that GSK-3 inhibition may have therapeutic potential for veterans suffering sustained TBI, they have only focused on the short-term effects of GSK-3 inhibition. To our knowledge, there has been no study exploring the long-term therapeutic potential of GSK-3 inhibition for sustained TBI. This study focuses on long-term therapeutic effects of GSK-3 inhibition on sustained TBI with attenuating the conversion of acute TBI neuropathology to chronic neurodegeneration. We will examine long-term therapeutic effects of GSK-3 inhibition on neuropathology, synaptic plasticity and cognitive deficits in the hippocampus of animals with sustained TBI triggered by repetitive concussions, using a murine mTBI model to explore the therapeutic potential of GSK-3 inhibition for veterans suffering sustained TBI. To inhibit GSK-3, we will use lithium, a typical GSK-3 inhibitor with additional neuroprotective properties and SB-216763, a specific GSK-3 inhibitor. We will pursue three specific aims as below. Specific Aim 1 (Neuropathological study): To determine whether repetitive concussions trigger long- term neurodegeneration, and GSK-3 inhibition attenuates the neurodegeneration. We will examine the neuopathological evidence of neurodegeneration including the number of degenerating neurons and the density of phosphorylated tau and A? in the hippocampus. Specific Aim 2 (Neurophysiological study): To examine whether repetitive concussions impair hippocampal synaptic plasticity, and GSK-3 inhibition reverses it. We will examine the long-term potential, the electrophysiological parameter of synaptic plasticity, and baseline synaptic transmission in the hippocampus. Specific Aim 3 (Cognitive behavioral study): To examine whether repetitive concussions produce cognitive deficits and whether GSK-3 inhibition improves the cognitive deficits. We will examine hippocampal- dependent spatial learning, using the Barnes maze method. At the completion of this study, we will be able to determine whether GSK-3 inhibition blocks the conversion of TBI acute neuropathology to neurodegenerative process and improves cognitive deficits and whether the drug effects on cognitive deficits are associated with its effects on hippocampal synaptic plasticity. This study will contribute to developing an effective therapeutic strategy for veterans who suffer sustained TBI.